Intralesional therapy is a less invasive method for the treatment of Peyronie's disease. The objective of this study was to evaluate intralesional injections of interferon alpha 2B (IFN-alpha-2B) as an effective alternative to the surgical treatment of Peyronie's disease. Twenty-one patients with Peyronie's disease were evaluated by use of penile duplex Doppler ultrasonography for cavernosal blood flows, degree of penile curvature, and plaque size. A questionnaire was given to all patients to assess sexual function. Each patient then received biweekly intralesional injections of 1 x 10(6) units of IFN-alpha-2B in 10 ml of normal saline over a period of 6 months. There was no placebo control group in this study. At the conclusion of the study, penile duplex Doppler imaging was repeated. A questionnaire was completed by all patients to assess changes in sexual function after treatment. Twenty patients completed the study, with all men reporting subjective softening of their plaques. Nine of 10 patients initially reporting penile pain with erection (90%) had resolution of their phallalgia while on study protocol. Thirteen patients (65%) had significant improvement in curvature, ranging from 20 to 90%. Seventeen patients (85%) demonstrated an objective 10 to 80% decrease in plaque size. Biweekly intralesional injections of Peyronie's plaques with IFN-alpha-2B resulted in a significant improvement in penile curvature, diminished pain, and reduced plaque size, and resulted in a subjective improvement in sexual function.